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plasmaMATCH: A clinical trial aiming to assess the safety and activity of targeted treatments in patients with advanced breast cancer where the targetable mutation is identified through circulating tumour DNA screening

Acronym

plasmaMATCH

Study hypothesis

plasmaMATCH aims to assess whether ctDNA screening can be used to detect patients with targetable mutations, and will assess the safety and activity of the targeted treatments in patients with targetable mutations identified at ctDNA screening.

Cohort C: AKT1 mutation identified in ctDNA screening in patients with ER positive breast cancer treated with AZD5363 and fulvestrant.400mg AZD5363 to be administered twice daily on a 7 day schedule of 4 days on treatment followed by 3 days off treatment.500mg fulvestrant IM Cycle 1 Days 1 and 15 and Cycle 2 onwards Day 1.

Cohort D: AKT activation basket with mutations of AKT1 in patients with ER negative breast cancer or AKT2/3 E17K, PIK3R1 or PTEN mutations or homozygous deletion of PTEN in both ER positive and ER negative breast cancer identified in ctDNA screening or in prior tumour sequencing conducted outside of plasmaMATCH, treated with AZD5363.480mg AZD5363 to be administered twice daily on a 7 day schedule of 4 days on treatment followed by 3 days off treatment.

For each cohort a cycle consists of 28 days.

Treatment will continue until disease progression according to RECIST v1.1. Patients will be assessed by CT scan every 8 weeks with assessment of response by RECIST v1.1. After 32 weeks patients will be assessed by CT scan every 12 weeks.

Intervention type

Other

Phase

Phase II

Drug names

Primary outcome measures

Confirmed objective response rate as defined by RECIST v1.1 for each cohort separately. A patient will be said to have had an objective response if they have a complete/partial response at any point during trial treatment.

Secondary outcome measures

1. Clinical benefit rate and progression free survival (PFS), defined as complete/partial response or stable disease as defined by RECIST v1.1 lasting at least 24 weeks. PFS will be measured from the date of entry into the treatment cohort until first date of either confirmed progressive disease according to RECIST criteria or death.2. Safety and tolerability of therapies will be assessed throughout the treatment period using the NCI CTCAE v4.03. Duration of response is measured from the time of first documentation of RECIST complete/partial response (whichever status is recorded first) until the first date that recurrence or progressive disease is objectively documented4. Frequency of mutations identified in ctDNA screening and the proportion of patients with a targetable mutation who enter the therapeutic component5. Agreement between ctDNA mutation status and tissue mutation status for patients entering the therapeutic component6. Pharmacokinetics in Cohort A assessed at Cycle 2-4 Day 1 and Cohort B assessed Cycle 1-4 Day 1

Overall trial start date

01/09/2015

Overall trial end date

31/12/2021

Reason abandoned

Eligibility

Participant inclusion criteria

1. Female2. Aged ≥ 18 years old3. Histologically confirmed invasive breast carcinoma4. Metastatic or recurrent locally advanced breast cancer that is not suitable for treatment with radical or curative intent5. Demonstrated progression of disease by radiological assessment or by clinical assessment within the last 6 weeks6. Measurable disease by RECIST v1.17. Patients must have completed at least one prior line of treatment for advanced breast cancer and/or relapse within 12 months of completing (neo)adjuvant chemotherapy. Patients with HER2 positive breast cancer must have been treated with at least two courses of HER2 targeted therapy in the advanced setting (or one course if no further courses of HER2 targeted therapy are available locally)8. Patient must either be suitable for a baseline biopsy of recurrent disease or have an archival biopsy of recurrent disease available. Patients are requested to consent to a baseline biopsy but if deemed unsafe by the Investigator, an archival biopsy of recurrent disease can be used instead. If it is deemed unsafe to proceed with baseline biopsy, and no archival recurrent disease biopsy is available, the patient will not be eligible for entry into the treatment cohort9. ECOG performance status ≤ 210. Life expectancy >3 months11. Patients must be surgically sterile, be postmenopausal or must agree to use effective contraception during the period of trial treatment and be willing to do so for 6 months following the end of trial treatment. Effective contraception is defined as double barrier contraception (e.g. condom plus spermicide in combination with a diaphragm, cervical cap or intrauterine device). Ovarian suppression with an LHRH agonist is not a method of contraception12. Patients of childbearing potential should have a negative serum pregnancy test within 14 days prior to initiation of trial treatment. 13. At least 4 weeks washout period after the end of trial treatment on a different cohort within plasmaMATCH14. Adequate haematological, renal and hepatic function as defined by: 14.1. Haematology: - Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0 x 109/L) - Platelet count ≥100,000/mm3 (≥100 x 109/L) - Haemoglobin ≥9g/dL (≥90g/L) 14.2. Renal function: - Serum creatinine ≤1.5 x upper limit of normal (ULN) and calculated creatinine clearance more than 30ml/min 14.3. Liver function tests: - Total bilirubin ≤1.5 ULN - Alanine aminotransferase (ALT) ≤3 ULN. In the presence of liver metastases ALT ≤5 ULN. For patients in Cohort B, C and D: aspartate aminotransferase (AST) ≤3 ULN. In the presence of liver metastases AST ≤5 ULN. 15. For patients with ER positive breast cancer in Cohorts A, B and C: EITHER postmenopausal, as defined by at least one of the following criteria: 15.1. Age >60 years15.2. Age <60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females15.3. Documented bilateral oophorectomy; medically confirmed ovarian failure.OR Pre-/peri-menopausal (i.e. not meeting the criteria for being postmenopausal) if being treated with an LHRH agonist that was commenced at least 4 weeks prior to Cycle 1 Day 1, and continues on the LHRH agonist throughout the trial period.NB. Additional eligibility criteria apply for entry into each treatment cohort.

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

Planned Sample Size: 1000; UK Sample Size: 1000

Participant exclusion criteria

1. Prior treatment with radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy, chemotherapy or IMPs during the previous 4 weeks (6 weeks for nitrosoureas, Mitomycin-C) before trial treatment, except for hormonal therapy with LHRH analogues, which are permitted, and bisphosphonates or RANK ligand antibodies that are permitted for the management of bone metastases2. Uncontrolled CNS disease (brain metastases or leptomeningeal disease). Patients with prior diagnosis of CNS metastases must be stable by clinical assessment having ceased steroids after prior treatment3. History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction within the last 6 months or ventricular arrhythmia. Patients with a history of any of the above listed cardiac conditions judged not to be clinically significant by the local investigator must be notified to the trial team at the ICR-CTSU for approval by the CI and/or Cohort Lead4. Ongoing toxic manifestations of previous treatments Grade ≥1. Exceptions to this are alopecia or toxicities which in the opinion of the Investigator should not exclude the patient. Such cases should be clearly documented in the patient’s notes by the Investigator5. Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks of the first dose of trial treatment6. Pregnant or breastfeeding7. Any condition that according to the treating physician may compromise the patient’s safety or the conduct of the trial8. Current malignancies of other types, with the exception of adequately treated in situ carcinoma of the cervix and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy and have no evidence of the disease for 3 years or more are eligible for the trial. NB. Additional eligibility criteria apply for entry into each treatment cohort.

Recruitment start date

15/12/2016

Recruitment end date

30/06/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

The Royal Marsden Hospital
Fulham Road
Chelsea
London
SW3 6JJ
United Kingdom

Trial participating centre

The Royal Marsden Hospital
Downs Road
Sutton
SM2 5PT
United Kingdom

Trial participating centre

Western General Hospital
Crewe Road South
Edinburgh
EH4 2XU
United Kingdom

Trial participating centre

Addenbrooke's Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Trial participating centre

Sponsor information

Organisation

Sponsor details

Royal Cancer Hospital 123 Old Brompton Road London SW7 3RP United Kingdom

Sponsor type

Hospital/treatment centre

Website

Organisation

The Royal Marsden NHS Foundation Trust

Sponsor details

Fulham Road London SW3 6JJ United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The main trial results for each treatment cohort will be published either separately or together in a peer-reviewed journal, on behalf of all collaborators. The results of the screening component, individual cohorts and translational research may be published together or individually.

IPD Sharing plan:The datasets generated during and/or analysed during the current study will be available upon request from plasmaMATCH-icrctsu@icr.ac.uk